tbuckley/cabot-search huggingface dataset:
Serum Amylase as a Biomarker for Proof-of-Concept Studies in Post Endoscopic Retrograde Cholangiopancreatography Pancreatitis Prevention
Authors: Romik P. Srivastava, Paul J. Nietert, John F.G. Bobo, Mona Haj, Nauzer Forbes, B. Joseph Elmunzer
Journal: Clinical Gastroenterology and Hepatology (2022)
Humoral immunity to SARS-CoV-2 elicited by combination COVID-19 vaccination regimens
Authors: Zijun Wang, Frauke Muecksch, Friederike Muenn, Alice Cho, Shuai Zong, Raphael Raspe, Victor Ramos, Brianna Johnson, Tarek Ben Tanfous, Justin DaSilva, Eva Bednarski, Camila Guzman-Cardozo, Martina Turroja, Katrina G. Millard, Pinkus Tober-Lau, David Hillus, Kai-Hui Yao, Irina Shimeliovich, Juan Dizon, Anna Kaczynska, Mila Jankovic, Anna Gazumyan, Thiago Y. Oliveira, Marina Caskey, Paul D. Bieniasz, Theodora Hatziioannou, Florian Kurth, Leif Erik Sander, Michel C. Nussenzweig, Christian Gaebler
Journal: The Journal of Experimental Medicine (2022)

The SARS-CoV-2 pandemic prompted a global vaccination effort and the development of numerous COVID-19 vaccines at an unprecedented scale and pace. As a result, current COVID-19 vaccination regimens comprise diverse vaccine modalities, immunogen combinations, and dosing intervals. Here, we compare vaccine-specific antibody and memory B cell responses following two-dose mRNA, single-dose Ad26.COV.2S, and two-dose ChAdOx1, or combination ChAdOx1/mRNA vaccination. Plasma-neutralizing activity, as well as the magnitude, clonal composition, and antibody maturation of the RBD-specific memory B cell compartments, showed substantial differences between the vaccination regimens. While individual monoclonal antibodies derived from memory B cells exhibited similar binding affinities and neutralizing potency against Wuhan-Hu-1 SARS-CoV-2, there were significant differences in epitope specificity and neutralizing breadth against viral variants of concern. Although the ChAdOx1 vaccine was inferior to mRNA and Ad26.COV.2S in several respects, biochemical and structural analyses revealed enrichment in a subgroup of memory B cell neutralizing antibodies with distinct RBD-binding properties resulting in remarkable potency and breadth.
Identification of Levels of Maternal HIV-1 RNA Associated With Risk of Perinatal Transmission
Authors: Ruth E. Dickover
Journal: JAMA (1996)

<h3>Objective.</h3> —To determine if there are levels of human immunodeficiency virus type 1 (HIV-1) associated with a high or low risk of perinatal transmission and to ascertain the mechanism by which zidovudine treatment reduces perinatal transmission. <h3>Design.</h3> —A nonrandomized prospective cohort study. <h3>Setting.</h3> —University medical center and two general hospital affiliates from May 1989 to September 1994. <h3>Patients.</h3> —Ninety-two HIV-1—seropositive women (95 pregnancies) and their 97 infants. <h3>Intervention.</h3> —Forty-two mothers (43 pregnancies) received zidovudine therapy during pregnancy and/or during labor and delivery. Eleven infants received prophylactic zidovudine for the first 6 weeks after delivery. <h3>Main Outcome Measure.</h3> —HIV-1 infection status of the infant. <h3>Results.</h3> —Twenty of the 97 infants were perinatally infected with HIV-1. Transmitting mothers were more likely to have plasma HIV-1 RNA levels higher than 50000 copies per milliliter at delivery than nontransmitting mothers (15 [75.0%] of 20 transmitters vs four [5.3%] of 75 nontransmitters;<i>P</i>&lt;.001). None of the 63 women with less than 20 000 HIV-1 RNA copies per milliliter transmitted. Twenty-two women treated with open-label oral zidovudine during gestation showed an eightfold median decrease in plasma RNA levels (median [25th and 75th percentile], 43043 [5699 and 63 053] copies per milliliter before zidovudine vs 4238 [603 and 5116] HIV-1 RNA copies per milliliter at delivery;<i>P</i>&lt;.001), and none transmitted. Four zidovudine-treated women with high HIV-1 levels transmitted despite the presence of zidovudine-sensitive virus in vitro in both the mothers and their infants. <h3>Conclusions.</h3> —Maternal HIV-1 RNA levels were highly predictive of perinatal transmission risk and suggest that certain levels of virus late in gestation and/or during labor and delivery are associated with both a high risk and a low risk of transmission. Our results also suggest that zidovudine exerts a major protective effect by reducing maternal HIV-1 RNA levels prior to delivery and that further strategies are needed to prevent perinatal transmission in women with high or increasing virus levels and/or zidovudine-resistant virus. (<i>JAMA</i>. 1996;275:599-605)
The Neurologic Basis of Fever
Authors: Jeffrey S. Flier, Lisa H. Underhill, Clifford B. Saper, Christopher D. Breder
Journal: New England Journal of Medicine (1994)

Fever is a complex, coordinated autonomic, neuroendocrine, and behavioral response that is adaptive and is used by nearly all vertebrates as part of the acute-phase reaction to immune challenge. Although the febrile response can be elicited by a wide variety of infectious organisms and may also occur during noninfectious inflammatory conditions, its manifestations are stereotyped and largely independent of the causative agent. Like other integrated responses, such as the regulation of energy metabolism, blood pressure and volume, and reproduction, fever depends on humoral cues from the body, is orchestrated largely by the hypothalamus, and involves the coordination of a wide . . .
Adverse Events Following Pertussis and Rubella Vaccines
Authors: Christopher P. Howson
Journal: JAMA (1992)

In August 1991, the Institute of Medicine released a report entitled<i>Adverse Effects of Pertussis and Rubella Vaccines</i>, which examined 18 adverse events in relation to diphtheria-tetanus-pertussis (DTP) vaccine and four adverse events in relation to the currently used rubella vaccine strain, RA 27/3. The committee spent 20 months reviewing a wide range of information sources, including case series and individual case reports, both published and unpublished, epidemiologic studies, studies in animals, and other laboratory studies. The committee found that the evidence indicates a causal relation between DTP vaccine and anaphylaxis and between the pertussis component of DTP vaccine and extended periods of inconsolable crying or screaming. The committee also reported that the evidence indicates a causal relation between the rubella vaccine and acute arthritis in adult women. The committee found the available evidence weaker but still consistent with a causal relation between DTP vaccine and two conditions—acute encephalopathy and hypotonic, hyporesponsive episodes—and between rubella vaccine and chronic arthritis in adult women. Estimated incidence rates of these adverse events following vaccination are provided, where possible. The committee found that the evidence does not indicate a causal relation between the DTP vaccine and infantile spasms, hypsarrhythmia, Reye's syndrome, and sudden infant death syndrome. The committee found insufficient evidence to indicate either the presence or absence of a causal relation between DTP vaccine and chronic neurologic damage, aseptic meningitis, erythema multiforme or other rash, Guillain-Barré syndrome, hemolytic anemia, juvenile diabetes, learning disabilities and attention-deficit disorder, peripheral mononeuropathy, or thrombocytopenia, and between rubella vaccine and radiculoneuritis and other neuropathies or thrombocytopenic purpura. The committee's evaluative methods are briefly described and a summary of research needs is provided. (<i>JAMA</i>. 1992;267:392-396)
Skin Cancer in Heart Transplant Recipients
Authors: Alida L. P. Caforio, Anna Belloni Fortina, Stefano Piaserico, Mauro Alaibac, Francesco Tona, Giuseppe Feltrin, Esmeralda Pompei, Luca Testolin, Antonio Gambino, Sergio Dalla Volta, Gaetano Thiene, Dino Casarotto, Andrea Peserico
Journal: Circulation (2000)

Background —The frequency of skin tumors of all types and specifically of squamous cell carcinoma (SCC) is increased in heart transplantation (HT), but the predisposing risk factors are controversial. Methods and Results —We studied 300 patients (age 49±15 years, 258 men, mean follow-up 4.6 years, follow-up range 1 month to 12 years) who were receiving standard double (cyclosporin plus azathioprine) or triple (cyclosporin plus azathioprine plus prednisone) therapy. The first-year rejection score was calculated for endomyocardial biopsy samples (International Society for Heart and Lung Transplantation grade 0=0, 1A=1, 1B=2, 2=3, 3A=4, 3B=5, and 4=6) and used as an indirect marker of the level of immunosuppression. Multivariate analysis (Cox regression) included age at HT, sex, skin type, first-year rejection score, presence of warts and solar keratosis, lifetime sunlight exposure, and first-year cumulative dose of steroids. The incidence of skin tumors of all types increased from 15% after 5 years to 35% after 10 years after HT according to life-table analysis. Age at HT of &gt;50 years ( P =0.03, RR=5.3), skin type II ( P =0.05, RR=2.6), rejection score of 19 ( P =0.003, RR=5.7), solar keratosis ( P =0.001, RR=6.9), and lifetime sunlight exposure of &gt;30 000 hours ( P =0.0003, RR=7.6) were risk factors for SCC. Conclusions —Older age at HT, light skin type, solar keratosis, greater sunlight exposure, and high rejection score in the first year were independently associated with an increased risk of SCC. The progressive increase in cancer frequency during follow-up and the association with high rejection scores suggest that both the length and level of immunosuppression may be relevant. Because cumulative immunosuppressive load is cumbersome to calculate, a high rejection score in the first year may provide a useful predictor for patients at risk.
Abstract 521: The role of the E3 ubiquitin ligase Parkin in clear cell renal cell carcinoma
Authors: Laura Kristin Esser, Vittorio Branchi, Farhad Shaker, Adrian Georg Simon, Carsten Stephan, Glen Kristiansen, Andreas Buness, Hubert Schorle, Marieta I. Toma
Journal: Cancer Research (2022)

Abstract Introduction: The E3 ubiquitin ligase Parkin has been described in several cancer entities, including clear cell renal cell carcinoma (ccRCC). Decreased Parkin expression is associated with poor prognosis. We aimed to clarify the biological role of Parkin in ccRCC and to evaluate its expression in a clinically characterized renal cancer cohort. Methods: We analyzed cell lines and clinically annotated patient material with qPCR (n=63), immunohistochemistry (n=262), LC-mass spectrometry and performed functional analyses in cell line models. Results: We found that overexpression of Parkin results in a less aggressive phenotype in the clear cell renal cell carcinoma cell line 786-O indicated by lower migration and invasion. Mass spectrometry revealed decreased levels of several proteins in Parkin expressing cells. One of these proteins was cyclin kinase subunit 2 (CKS2). The introduction of a C431S mutation in the catalytic domain of the Parkin gene abolished the effect of decreased migration. In addition, knockdown of CKS2 in cells lacking Parkin caused decreased migration suggesting that the effect of Parkin is CKS2 mediated. Furthermore, the correlation of CKS2 and tumor grading is highly significant and high levels of CKS2 are associated with shorter survival times. Conclusions: Parkin plays a major role in ccRCC biology, regulation cell migration and invasion, possibly exerted by CKS2 signaling. In consequence CKS2 appears to be an interesting prognostic biomarker in clear cell renal cell carcinoma and might also serve as a new therapy target. Citation Format: Laura Kristin Esser, Vittorio Branchi, Farhad Shaker, Adrian Georg Simon, Carsten Stephan, Glen Kristiansen, Andreas Buness, Hubert Schorle, Marieta I. Toma. The role of the E3 ubiquitin ligase Parkin in clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 521.
Abstract 4231: Hypoxia reduction in tandem with anti-angiogenic therapy remodels the pancreatic tumor microenvironment
Authors: Arthur J. Liu, Michael A. Curran
Journal: Cancer Research (2022)

Abstract Pancreatic cancer patients remain largely unresponsive to single agent immune checkpoint blockade (ICB) therapy. This refractory state originates from PDAC’s unique immunosuppressive microenvironment that is densely populated by suppressive myeloid cells, exhibits poor vascularity, and is highly hypoxic. We previously showed that the hypoxia-activated prodrug TH-302 (Evofosfamide) reduces intratumoral hypoxia through a tissue remodeling process, initiates tumor vasculature reorganization, and sensitizes aggressive, spontaneous murine models of prostate cancer to ICB. In a clinical trial testing the combination of Evofosfamide with cytotoxic T-lymphocyte-associated protein (CTLA-4) blockade (NCT03098160) a subset of metastatic, immune checkpoint blockade refractory patients showed prolonged progression free survival. While these studies highlight hypoxia reduction as therapeutically tractable, we lack complete understanding of the contribution of the tumor vasculature to hypoxia reduction therapy, as well as the downstream consequences of hypoxia reduction on the cellular composition of the tumor microenvironment and the responsiveness to immunotherapy. We used a transplantable, orthotopic pancreatic tumor model derived from Kras+/LSL-G12D; Trp53+/LSL-R172H; Pdx1-Cre mice and a syngeneic prostate tumor model to study tumor responses to hypoxia-reduction, anti-angiogenic therapy, and combination immunotherapy. We find that Evofosfamide with anti-VEGFR-2 (DC101) significantly extends mouse survival. Combination therapy reduces intratumoral hypoxia, improves vessel integrity, and increases intratumoral DNA damage. In response to the improved metabolic microenvironment, CD8 T cells gain enhanced effector function and lose expression of exhaustion-associated features. Like other anti-angiogenic regimens, combination Evofosfamide and DC101 leads to an increased frequency of PD-L1 expressing cells within the tumor, however blockade of PD-1 failed to prolong survival. Bulk-tumor RNA sequencing and tumor infiltrating lymphocyte analysis implicates immature myeloid cells as mediators of resistance. Re-education of the infiltrating myeloid stroma with CD40 agonist could improve responses to hypoxia-reducing, anti-angiogenic therapy. Put together, these data indicate that targeted hypoxic reduction with anti-angiogenic therapy remodels the pancreatic tumor microenvironment. In this setting, CD40 agonist over PD-1 blockade provides an additive benefit in prolonging mouse survival. Citation Format: Arthur J. Liu, Michael A. Curran. Hypoxia reduction in tandem with anti-angiogenic therapy remodels the pancreatic tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4231.
Abstract 5567: hYP218 CAR-T cells targeting a membrane-proximal epitope of mesothelin are highly effective against mesothelin expressing cancers
Authors: Sakshi Tomar, Jingli Zhang, Nan Li, Ira Pastan, Mitchell Ho, Raffit Hassan
Journal: Cancer Research (2022)

Abstract Background and Hypothesis: Mesothelin is an attractive target for CAR-T cell therapy since it is highly expressed in many solid tumors but has limited expression on normal human tissues. However, anti-mesothelin CAR-T cells have shown limited efficacy in patients. Since most antibodies to mesothelin bind the membrane distal epitopes we generated antibodies that bind mesothelin in a membrane-proximal region. We hypothesize that CAR-T cells recognizing a membrane proximal epitope on mesothelin will be more efficacious. Study Design: We developed CAR-T cells targeting a membrane-distal (SS1CAR-T) and a membrane-proximal epitope (hYP218 CAR-T) of mesothelin. Using mesothelin-expressing cancer cell lines, anti-tumor efficacy of CAR-T cells was assessed in vitro by measuring direct killing of tumor cells by the CAR-T cells and quantifying cytokine-release by the CAR-T cells. In vivo anti-tumor efficacy of CAR-T was determined in NSG mice using three different solid tumor models of high-mesothelin expression: ovarian cancer (OVCAR-8), pancreatic cancer (KLM-1), and mesothelioma patient-derived xenograft (NCI-Meso63). Blood and tumor infiltration of CAR-T cells in vivo was determined via flow cytometry analysis. Results: Upon co-culture with tumor cells with high mesothelin expression (A431-H9, OVCAR-8, KLM-1, H226, NCI-Meso63, NCI-Meso29), hYP218 CAR-T cells killed cancer cells more efficiently than SS1 CAR-T cells, with a 2-4-fold lower ET50 value (Effector to Target ratio for 50% killing of tumor cells). Additionally, compared to SS1 CAR-T cells, hYP218 CAR-T cells secreted significantly higher level of cytokines (IL-2, TNFα, IFNγ) in a co-culture with tumor cells. In three solid tumor models, single treatment of tumor-bearing mice with hYP218 CAR-T cells lead to improved tumor response and survival compared to SS1 CAR-T, with complete regression of OVCAR-8 and NCI-Meso63 tumors. Compared to SS1 CAR-T cells, higher hYP218 CAR-T cell infiltration was detected both in the blood and tumors isolated from hYP218 CAR-T treated mice seven days post-treatment. Conclusion: We demonstrate that hYP218 CAR-T cells targeting a membrane-proximal epitope of mesothelin are more potent than similar CAR-T cells targeting a membrane distal epitope. Increased accumulation of hYP218 CAR-T cells in the tumor may explain their increased efficacy. These results support its clinical development to treat patients with mesothelin expressing cancers. Citation Format: Sakshi Tomar, Jingli Zhang, Nan Li, Ira Pastan, Mitchell Ho, Raffit Hassan. hYP218 CAR-T cells targeting a membrane-proximal epitope of mesothelin are highly effective against mesothelin expressing cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5567.
Abstract 5558: Discovery of a novel Claudin 6 X 4-1BB bispecific antibody with potent anti-tumor activity through conditional 4-1BB activation
Authors: Jian Li, Wenqing Jiang, Yan Liu, Zhengyi Wang, Xi Chen, Taylor B. Guo
Journal: Cancer Research (2022)

Abstract Background Claudin 6 (CLDN6) is a tight junction transmembrane protein normally only expressed during embryonic development, but is aberrantly expressed in a variety of tumors, including ovarian cancer, testicular cancer, hepatocellular and lung adenocarcinoma. Here, we generated a CLDN6 X 4-1BB bispecific antibody (BsAb) which could conditionally activate T cells through 4-1BB stimulation upon CLDN6 engagement, positioning it as a potential novel immunotherapy for ovarian cancer and other CLDN6 positive tumors. Methods CLDN6 X 4-1BB BsAb was evaluated for its antigen binding through cell-based binding assay. In vitro function of the antibody was confirmed in a 4-1BB signaling reporter assay and primary human PBMC assay. In vivo efficacy of the antibody was further demonstrated in 4-1BB humanized syngeneic mouse model. Ex vivo analysis of tumor infiltrating and peripheral immune cells was conducted by FACS. Safety parameters such as liver enzymes and pathology upon antibody administration were also assessed. Results CLDN6 X 4-1BB BsAb showed strong binding to several ovarian cancer cell lines with different levels of CLDN6 expression. Functional evaluation of CLDN6X4-1BB BsAb indicated that the activation of 4-1BB signaling was dependent on CLDN6 expression on tumor cells and the activity was stronger than reference 4-1BB monoclonal antibody urelumab. In a humanized 4-1BB mouse model, CLDN6X4-1BB BsAb showed tumor growth inhibition superior to the combination of anti-CLDN6 and anti-4-1BB monospecific antibodies, and the treatment effect was associated with an increase in tumor infiltrating CD45 and CD8 cells as well as CD8/Treg ratio. From the safety perspective, there were no significant changes in liver enzymes or liver histopathology following repeated BsAb administration, suggesting little risks for liver toxicity commonly induced by other 4-1BB agonist antibodies. Conclusions We have successfully generated a novel CLDN6-targeted 4-1BB bispecific antibody which could induce potent 4-1BB stimulation and anti-tumor activity in a CLDN6-dependent manner while minimizing the risk of liver toxicity. Taken together, these data support further development of CLDN6 X 4-1BB bispecific antibody towards IND and clinical trial in 2022. Citation Format: Jian Li, Wenqing Jiang, Yan Liu, Zhengyi Wang, Xi Chen, Taylor B. Guo. Discovery of a novel Claudin 6 X 4-1BB bispecific antibody with potent anti-tumor activity through conditional 4-1BB activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5558.
Abstract 5322: The antitumor activity and immumodulatory effect of a novel phosphodiesterase 10 inhibitor
Authors: Md Yeashin Gazi, Caitlin Brandle, Ogacheko Okoko, Xi Chen, Adam Keeton, Yulia Maxuitenko, Gary Piazza, Gang Zhou
Journal: Cancer Research (2022)

Abstract Phosphodiesterase 10 (PDE10) is overexpressed in several types of cancer, including lung, breast and colon cancers. It has been proposed that inhibitors targeting PDE10 may exhibit antitumor activities. Previous studies have shown that PDE10 inhibition can selectively activate cGMP-dependent protein kinase to suppress oncogenic β-catenin signaling in colon cancer cells. However, the impact of PDE10 inhibitors on tumor cell immunogenicity has not been examined. Here we report the antitumor activity and immunomodulatory effect of a novel PDE10 inhibitor (ADT030) in preclinical models. We show that administration of ADT030 significantly inhibited the growth of murine colorectal cancer CT26. In a metastatic breast tumor model (4T1), ADT030 administration not only delayed the growth of the primary tumor but also reduced tumor metastasis, resulting in prolonged mouse survival. Immunological analysis revealed profound reduction of MDSCs in mice, and improved T cell tumor infiltration and function after ADT030 treatment. Moreover, the combination of ADT030 and anti-PD-1 antibody therapy led to further improved tumor growth control and mouse survival. These results implicate PDE10 as a promising therapeutic target and its inhibition may enhance the efficacy of cancer immunotherapy. Citation Format: Md Yeashin Gazi, Caitlin Brandle, Ogacheko Okoko, Xi Chen, Adam Keeton, Yulia Maxuitenko, Gary Piazza, Gang Zhou. The antitumor activity and immumodulatory effect of a novel phosphodiesterase 10 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5322.